*1.2. Ayurveda*

Ayurveda (translated as "the science of life") is one of the oldest medical systems in the world. Its origins date back to thousands of years ago in the Vedic era in the Indian subcontinent. Ayurveda defines life, "ayu", as a union of mind, body, spirit, and senses and health as the balanced state of these factors [17]. The wisdom of Ayurveda is based on three major classical texts, namely Charaka Samhita, Sushruta Samhita, and Ashtanga Hridaya, plus six minor texts. These ancient texts give detailed descriptions of over 700 herbs and 6000 formulations in addition to descriptions of various diseases, diagnostic methods, and dietary and lifestyle recommendations [18]. Ayurvedic treatment focuses on restoring the balance of the disturbed body–mind matrix through diet and behavioral modifications, administration of drugs, and detoxification and rejuvenation therapies. The branch of Ayurvedic science that deals with herbs and their qualities is called Dravyaguna vigyan. Ayurvedic formulations are prepared based on this knowledge and largely comprise herbs. Classical and proprietary Ayurvedic formulations may consist of a single herb or mixtures of many herbs in any form, viz., juice, extract, powder, tablet, or decoction.

Although there is no direct correlate for hypercholesterolemia in Ayurveda, dyslipidemia can be considered close to the Ayurvedic terms "medovriddhi" or "medodushti". The main herbs used in Ayurveda to reduce cholesterol are garlic (*Allium sativum*), guggulu

(*Commiphora mukul*), and arjuna (*Terminalia arjuna*) [19–21]. The authors of this paper looked into the most common Ayurvedic products used for high cholesterol. Either used alone or in combination with other herbs, these three herbs are found in most of the Ayurvedic formulations with some additional ingredients. The list of additional ingredients used in combination with the above-mentioned herbs may include pushkarmoola (*Inula racemosa*), ginger, turmeric, shilajit, punarnawa (*Boerrhavia diffusa*), triphala, *Nigella Sativa*, garcinia, *Cyperus rotundus,* and licorice. Many published clinical trials on Ayurvedic herbs for hypercholesterolemia have presented some evidence that these formulations are effective in reducing cholesterol [19–21]. However, many times, such RCTs are often limited by their study designs, sample sizes, or lack of validity and/or generalizability [22]. Recently, researchers have also been encouraged to apply principles of evidence-based medicine to Ayurveda [17,23].

#### *1.3. Need for Study*

Although there are many reviews for individual Ayurvedic herbs [20,24–27], there is a strong need to conduct a review to systematically summarize the available evidence as well as identify the strength of this evidence. Our preliminary search yielded one systematic review on the use of Ayurvedic herbs for Hyperlipidemia. Singh et al. (2007) [16] conducted a systematic review on Ayurvedic herbs and collateral treatments for hyperlipidemia and concluded that a significant number of researches show strong efficacy of Ayurvedic herbs for hyperlipidemia, with minimal reports of side effects. Despite its comprehensiveness, the review was limited by the use of randomized and quasi-randomized studies, arbitrary scoring methods to categorize studies, and a lack of systematic summarization of results using meta-analyses. With the current study, we aim to critically analyze the available evidence on potential benefits and harms of Ayurvedic herbs for hypercholesterolemia using Cochrane guidelines for conducting systematic reviews and meta-analyses. The current study adds on the systematic review of Singh et al. (2007) by providing strong conclusions using statistically accurate methods to establish unambiguous evidence.

#### **2. Materials and Methods**

The current review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [28], and a protocol was previously published with the Cochrane database [29] for systematic reviews and meta-analysis [30].

#### *2.1. Search Strategy*

A systematic literature review of all studies published and accessible through December 2020 was performed by two authors (DG and RS) using the following databases:


(publication of Gujarat Ayurveda University, India), *The International Journal for Ayurveda Research, Journal of Drug Research in Ayurveda, Journal of Ayurveda and Integrative Medicine*, *Ancient Science of Life*, *International Journal of Ayurveda and Pharma Research*, A Bibliography of Indian Medicine (ABIM), Digital Helpline for Ayurveda Research Articles (DHARA), *Indian Heart Journal*.

iii. Other resources. Every effort was made to identify other potentially eligible trials or ancillary publications by searching the reference lists of retrieved included trials, systematic reviews, meta-analyses, and health technology assessment reports. In addition, study authors of included trials were contacted to identify any further studies that may have been missed.

Selection of studies: Abstract, title, or both of every record retrieved was scanned to determine which studies should be assessed further. All potentially relevant articles were investigated as full text. In case of any discrepancy, consensus was made with a discussion between all authors. An adapted PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram was presented showing the process of study selection [28]. For studies fulfilling inclusion criteria, key participant and intervention characteristics were abstracted and data on efficacy outcomes and adverse events were reported using standard data extraction templates as supplied by the Cochrane Metabolic and Endocrine Disorders Group and Cochrane Hypertension Group. Efforts were made to find the protocol of each included study, and primary, secondary, and other outcomes are reported in comparison with data in publications in a joint appendix, "Matrix of study endpoint (publications and trial documents)". Duplicate studies, companion documents or multiple reports of a primary study, and yield of information was maximized by collating all available data, and the most complete dataset aggregated across all known publications was used. In case of doubt, priority was given to the publication reporting the longest follow-up associated with primary or secondary outcomes of these studies.

Types of studies: All relevant randomized controlled trials (RCTs) irrespective of publication status, blinding, and language were included. The original authors were contacted to confirm the details on random list generation and allocation concealment when possible. Quasi-randomized or non-randomized and studies shorter than 3 weeks in duration were not included. However, those studies were separately analyzed to document the available evidence. Trials that studied non-pharmacological approaches of Ayurveda (for example, Panchakarma) as a single intervention were excluded. Where participants were given some other treatments such as statins, in addition to Ayurvedic herbal preparations, the studies were included if the treatment was evenly distributed between groups and it was only Ayurvedic treatment that was randomized.

Participants: All studies where participants have high blood cholesterol levels (diagnosed as per the standard laboratory tools) without restrictions of age, gender, ethnicity, and other medical conditions were included. Study participants were considered eligible irrespective of the duration and chronicity of the condition and/or treatment duration. Studies with participants having a mean total cholesterol level greater than 200 mg/dL (5.2 mmol/L) or LDL cholesterol > 130 mg/dL were included. ATP III suggests above readings are the levels of borderline high risk (NCEP, 2001). Studies where participants are not subject to standard laboratory tests to diagnose hypercholesterolemia were not included.

Interventions: The following comparisons of intervention versus control/comparator were carried out.


2.1.1. Comparison Groups

